Project Summary Sickle cell disease (SCD), one of the most common inherited disorders, effects an estimated 100,000 Americans, mostly of African-American descent, as well as millions globally. Despite current preventative/treatment modalities, SCD morbidity is associated with premature mortality and substantial financial and quality of life costs. A hallmark of SCD is the vaso-occlusive pain crisis, a recurrent, unpredictable, and debilitating event. Demographic factors, genotype, psychosocial factors, socioeconomic status (SES) and environmental exposures have been linked with SCD pain crises. Although the precise pathophysiology of vaso-occlusive crises is not fully understood, identified mechanisms are markedly similar to those postulated for the well-established associations of cardiovascular morbidity and mortality with ambient air pollution exposures. While it is biologically plausible that exposure to ambient air pollution could be associated with increased risk of sickle cell pain crises, epidemiologic research is very limited. The proposed study takes advantage of an existing statewide hospital administrative dataset; complex, innovative spatio-temporal particulate matter (PM) and component exposure models developed for previously funded research; hierarchical Bayesian ozone exposure models developed by the US EPA; and the case crossover study design. We will examine whether hospitalizations and emergency department visits for vaso-occlusive pain crises among SCD patients are associated with short-term exposures to ambient air pollutants. The proposed study will, to the best of our knowledge, be the first to evaluate comprehensively the effects of ozone, PM2.5, and biologically relevant traffic-related PM components on SCD vaso-occlusive pain crises among a statewide population with a high rate of reported SCD-related mortality. The results of our study could advance understanding of pathophysiological responses to air pollution among a population experiencing debilitating and costly adverse outcomes.